The objectives of this project are to assess the relative importance of increased oxidative stress, hyperglycemia, and dyslipidemia for endothelial dysfunction in Type 2 diabetes mellitus, and to investigate potential interventions to restore endothelial function. In order to achieve these objectives, we plan to examine endothelium-dependent brachial artery vasodilation non-invasively in 250 patients with adult onset diabetes mellitus and matched non-diabetic control patients using a recently developed, brachial ultrasound method. This measure of endothelial function will be related to plasma lipids, plasma measures of glycemic control (fasting blood glucose and hemoglobin A-1c), and plasma markers of oxidative stress (F2 isoprostanes, LDL lag phase, antioxidant levels, advanced glycosylation end- products) in a multivariate regression model. We will also examine the relationship between microalbuminuria and other markers of vascular dysfunction. Mechanisms of endothelial dysfunction will be further investigated using invasive brachial arterial infusion techniques and venous occlusion plethysmography. In carefully characterized subgroups of patients, we will define the effects of metabolic abnormalities in Type 2 diabetes on endothelial vasomotor function. In particular, we will test the hypothesis that increased production of reactive oxygen species contributes to impaired vasomotion. Based on the findings of these initial investigations, we will use specific interventions to restore endothelial function in diabetic patients such as reduction of oxidative stress (alpha tocopherol and ascorbate), lipid-lowering (simvastatin and gemfibrozil), and improved glucose control (initiation of insulin). It is our hypothesis that hyperglycemia and hyperlipidemia interact to disturb the function of endothelial cells by increasing vascular oxidative stress. There is strong evidence that endothelial dysfunction contributes to the atherogenic process and to the clinical expression of ischemic vascular disease. For these reasons, study of endothelial function in diabetic patients is likely to provide insight into the causes and management of ischemic vascular disease in this population.